Digitally‐enabled, patient‐centred care in rhinitis and asthma multimorbidity: The ARIA‐MASK‐air® approach

Abstract MASK‐air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK‐air® is a Good Practice of DG Santé on digitally‐enabled, patient‐centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co‐operation and Development). MASK‐air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK‐air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as‐needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom‐medication score (ARIA‐EAACI‐CSMS) has been validated for clinical practice and trials. The implications of the novel MASK‐air® results should lead to change management in rhinitis and asthma.


| INTRODUCTION
Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the healthcare system into integrated care with organisational health literacy.
Smart devices and Internet-based applications (apps) are largely used in AR 1 and may help to address some of the unmet needs in the real-life assessment of patients' treatment choices and disease control. However, these new tools first of all need to be tested for privacy rules, acceptability, usability, validity and cost-effectiveness.
Second, they should be evaluated in the frame of the digital transformation of health, their impact on healthcare delivery and health outcomes so that mHealth tools may enable the digital transformation of health and care, empowering citizens and building a healthier society. 2 AIRWAYS-ICPs (Integrated care pathways for airway diseases) launched a collaboration to develop digitally-enabled and multisectoral care pathways (ICPs). 3   Allergic rhinitis (AR), one of the most common chronic conditions globally, often co-occurs with asthma and conjunctivitis (multimorbidity). It causes major burden and disability worldwide with substantial economic cost. 7,8 AR management is complex, as many possible interventions are available including allergen avoidance, pharmacotherapy and allergen-specific immunotherapy (AIT). [9][10][11][12] Many evidence-based guidelines for AR have improved its understanding and management. [12][13][14][15] They all propose long-term continuous treatment for subjects with persistent symptoms. However, guidelines are mostly based on randomised controlled trials (RCTs), typically undertaken on highly-selected samples of the population, often with limited/unclear generalisability to routine care contexts. [16][17][18] Many patients are, however, dissatisfied with their treatment: despite high adherence to various treatment options, their symptoms remain poorly controlled. Moreover, adherence to treatment is usually poor in AR, even when using mHealth supporting tools. 19 Large observational implementation studies are needed to triangulate RCTs and to better understand AR phenotypes and management. They reflect 'real-world' everyday use and practice more closely than RCTs in terms of patient heterogeneity as well as the variety of medical interventions. 20 Observational studies with direct patient data (often known as real-world data) examine the possible effect of a treatment on subjects where the investigator has no control over the experiment and cannot randomise subject allocation. 21 However, they provide clinically-relevant information complementing RCT information. mHealth apps are a valuable source of direct patient data and offer new insights into chronic diseases.
As a tool for the implementation of AIRWAYS-ICPs, MASK-air ® (Mobile Airways Sentinel NetworK for airway diseases) is an mHealth app. It provides direct patient data and offers new insights into AR phenotypes and management in a patient-centred approach in order to facilitate shared decision making. 22 MASK-air ® is a Good Practice of DG Santé for digitally-enabled, patient-centred care pathways. 23  Many patients with AR and/or asthma are: � uncontrolled � not satisfied by their treatment � In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Healthcare costs should be sustainable despite the increased prevalence of AR and the availability of new expensive treatments (e.g., biologics) for asthma multimorbidity.
� Most economies are struggling to deliver modern health care effectively, both in terms of � insufficient healthcare work force and � increasing costs.
� There are wide disparities within and between countries leading to underserved populations with increased burden.

| Mission
� There is a need to support the transformation of the healthcare system into integrated care with organisational health literacy centred around the patient.
� mHealth apps and Internet-based applications used in AR and asthma may help to address some of the unmet needs in the real-life assessment of patients' treatment choices and disease control.
� However, these new tools need: � Firstly, to be tested for privacy rules, acceptability, usability and cost-effectiveness.
� Secondly, to be evaluated in the frame of the digital transformation of health to assess: � Their impact on healthcare delivery and health outcomes � so that mHealth tools may enable the digital transformation of health and care � empowering citizens � and building a healthier society.
� The ultimate goal is change management for AR and asthma multimorbidity.

| Vision
To provide a novel cost-effective strategy developing digitallyenabled care pathways centred around the patient � Using validated and user-friendly mHealth tools.
� Based on patients' needs, beliefs, cultural differences and behaviour.
� To reduce the gaps between the patients and the physicians (to improve shared decision making).
� To provide next-generation care pathways from the citizens to the specialist and the policy maker.
� To propose novel strategies with available treatments (and Value-Added Medicine).
� To improve patients' health and well-being and reduce indirect costs.
� This approach may need to define novel phenotypes with different medical needs.
The strategy should be deployed in the EU and globally (developed and developing countries) in order to reduce health and social inequalities within and between countries.

| Objectives
The overarching objectives of MASK-air ® are (i) to propose a multisectoral care pathway to transform healthcare systems in a costeffective manner in rhinitis and asthma using mHealth tools acceptable for the patient and the healthcare worker and (ii) to strengthen planetary health (Figure 1).

| Strategic overview
The vision of MASK-air ® has led to a strategic overview that was initiated by ARIA in 1999 (Table 1).

| mHEALTH APPS IN RHINITIS
Few apps addressing AR patients have been evaluated. This has made their selection difficult. We have introduced a new approach to market research for AR apps based on the automatic screening of the Apple App and Google Play stores. 26 A JavaScript programme has been devised for automatic app screening and applied in a market assessment of allergic rhinitis self-management apps. We searched the Google Play and Apple App stores of three countries (USA, UK, Australia) with the following search terms: hay fever, hayfever, asthma, rhinitis, allergic rhinitis. Apps were eligible if symptoms were evaluated. Three apps could be used in 2021, according to criteria required for the study, and two for the purposes of the Combined Symptom-Medication Score (CSMS) (AllergyMonitor 27,28 and MASK-air ® ).

| Characteristics and geographical distribution
MASK, the Phase 3 ARIA initiative, was developed from the MASKair ® app to a flexible e-platform for allergic diseases and asthma. It is operational in 29 countries and 19 languages (Figure 2). Over 58,000 users have been registered.
MASK includes: (i) a freely available app (MASK-air ® , formerly the Allergy Diary, free on Android and iOS), 29 (ii) tools to support healthcare professionals in shared decision making through an interoperable electronic decision support system (e-CDSS), 30 (iii) a web-based interoperable questionnaire for physicians, 31 (iv) a questionnaire on asthma and rhinitis (CARAT: Control of Allergic Rhinitis and Asthma Test) for screening allergic diseases and assessing their control 32,33 and (v) a sentinel network for air quality (air pollution) and pollen seasons. 34 The MASK-air ® app is centred around the patient. 35  It follows the General Data Protection Regulation (GDPR) which regulates the processing of personal data in the European Union (EU). 36 Geolocation also follows the GDPR. 37

| Maturity level
The Technology Readiness Level (TRL) 38 has been assessed ( Table 2).

| Validation
COSMIN guidelines 50 were assessed for the VAS scales used in MASKair ® (Table 3). There was an excellent internal consistency (Cronbach's test >0.84, test-retest >0.7), reliability (>0.9) and acceptability. In addition, the VASs had a good sensitivity when users (n = 521) answered them twice in <3 h. In a second study, 51 intra-rater reliability was tested (intraclass correlation coefficients, ICCs) and ranged  52 to assess the intra-individual response variability (IRV) index. 52 The independency of VAS questions was assessed using the Bland and Altman regression analysis. 75 The analysis showed that all VAS measurements were independent. 59

| Achievements
The overall results concerning methodological validation and achievements are presented in Table 3.

| Visual analogue scales
Even though there is an independence of data in MASK-air, all PROMs are highly correlated ( Figure 3). 40 There are two statistical approaches for determining a cut-off value: PROM-oriented (percentiles) and outcome-oriented (VAS work and EQ-5D). Moreover, it is important to determine the 'no symptom' level (Sousa-Pinto, submitted) ( Table 4).

| Electronic daily combined symptommedication score (ARIA-EAACI CSMS)
Validated combined symptom-medication scores (CSMSs) are needed to investigate the effects of AR treatments.
The gold standard for the assessment of a CSMS requires a tool that does not include symptoms or medications and, if possible, has an economic impact. Such tools include, among other end points, work productivity and quality-of-life.

Rhinitis platform TRL References Asthma platform TRL References
App for rhinitis and multimorbidity (MASK-air ® ): available in 28 countries, 17 languages, >50,000 users 9 35,39,40 Adaptation of the MASK-air app for SA developed and tested by the DHE SA-TWINNING 8 PROMs for rhinitis 9 PROMS for asthma 9 41 CARAT questionnaire for screening and control of rhinitis and asthma, 20 countries 9 32,[42][43][44] The same questionnaire will be used 9 32,42,43 e-physician questionnaire for rhinitis (available on the MASK-air website) deployed in 28 countries and 20 languages 9 31 Adaptation of the MASK questionnaire for SA developed by the DHE SA-TWINNING   6 Electronic clinical decision support system in English for rhinitis 8 30 Embedding air quality (outdoor air pollution) and pollen data in MASK-air ® (POLLAR) 9 45 Alerts for air pollution and pollens predicting asthma exacerbations 5 NA Alerts for rhinovirus predicting asthma exacerbations 4 46,47 EAACI-ARIACARE-digital network (28 countries, 20 languages) 9 The same network will be used 9 Symptom-medication score for rhinitis 9 48 Daily control-medication score for asthma 5 NA Sensors for pulmonary function 5 Embedding artificial intelligence in MASK-air ® 2 Embedding artificial intelligence in MASK-air ® 2 GDPR for the app 9 37,49 GDPR for the app 8 37,49 BOUSQUET ET AL.  control of allergic diseases (CARAT). 67 The following scores were defined and tested (Table 5) and then validated in different countries.

Study name
There was a very high reproducibility of CSMSs in the 9 countries where there were enough data to provide statistical analyses ( Figure 4). � There are potential measurement biases when using apps since the information collected is usually restricted and less complete than when using more detailed paper or web-based questionnaires.

| Transfer of innovation
� App users may be a selected subset and are not fully representative of all AR patients in the general population. Higher education or specific age ranges might apply.
� Precise patient characterisation is impossible via an app used in real life. However, every study in MASK-air has produced highlyconsistent results with a clear perspective.
� The diagnosis of rhinitis, asthma and/or conjunctivitis is not confirmed by a physician. Users self-report symptoms but the baseline questionnaire on rhinitis and conjunctivitis as well as CARAT for rhinitis and asthma help the diagnosis.
� Information biases associated with the underreporting of medication use are possible.
� There is an unsupervised input of data.
� Observational studies can only be hypothesis-generating and findings should be confirmed by proper studies. Although analyses have been carried out in over 28,000 users in 27 countries, a replication study is not available. � The MASK-air and ARIACARE networks.

| Strengths
� The MASK-air ® app is available in 29 countries (20 languages) and is inter-operable with a web-based physician's questionnaire 82 and an e-CDSS for AR. 30 � It currently (September 2022) includes over 58,000 users and around 600,000 days ( Figure 5). � The rhinitis assessment is nearing completion in over 20,000 users (current paper) and the asthma assessment has been initiated in over 8000 users.
� In asthma, all categories of patients are included and the database can be used to compare asthmatics of different severity grade.

Limitations of the study:
Overall limitations.

| Confirmation by canonical epidemiologic and genetic studies
mHealth apps are only tools that generate hypotheses. They therefore need to be confirmed in classical epidemiologic studies. Differences between AR alone and AR associated with conjunctivitis were already known. [83][84][85] However, new studies carried out using MASKair ® data have shown that (i) ocular symptoms are more common in polysensitised patients whether or not they have asthma, 86 (ii) ocular symptoms are associated with the severity of nasal symptoms, 87,88 (iii) it is important to consider ocular symptoms in severe asthma 87 and (iv) the severity of allergic diseases increases with the number of allergic multimorbidities. 89 A genomic approach showed differences between diseases alone and multimorbidity. 90

| 'Asthma' key words (cross-sectional study)
In a cross-sectional asthma cluster analysis, an extreme asthma phenotype was found independently of treatment. This phenotype was

F I G U R E 4 Reproducibility of CSMSs in different countries (from 67 ).
associated with high rhinitis, high conjunctivitis and high CSMS. It can be separated into 2 groups (patients with and without a treatment for asthma). Patients with treated uncontrolled severe asthma have more uncontrolled rhinitis than untreated ones (Figure 7).

| 'Rhinitis' key words (longitudinal study)
In a longitudinal rhinitis cluster analysis, two extreme allergy phenotypes were identified ( Figure 6). One was associated with uncontrolled asthma (U1) and a second one with controlled asthma (U2).
The first phenotype (U1) was unchanged when several weeks were analysed, whereas the second one (U2) was unstable and often associated with uncontrolled asthma when several weeks were analysed. This study confirms that the 'extreme' allergy phenotype is found in patients and that the three diseases are associated with a significant impact on work productivity (Figure 7).

Limitations of the studies:
Only patients with asthma and nasal symptoms were studied.

| Confirmation of the distinct rhinitis and rhinitis + asthma phenotypes
A study compared reported symptoms and medication use in rhinitis

| Adherence to rhinitis treatment is poor
An observational cross-sectional study has assessed the adherence to treatment in AR patients using MASK-air. 57

Limitations of the study:
We only considered the users who reported over 6 days of MASK-air use. We did not analyse the type of treatment due to its great variability. We did not include a questionnaire on medication adherence.

| Patients treat themselves when they are not well
Medication use peaked during the pollen season in all of the inves-

| Many patients use OTC medications and selfmedicate
A large number of patients use OTC medications and self-medicate.
In Europe, users reported an annual average of 2.7 drugs, with 80% reporting two or more ( Figure 9).

| Switching of treatments is common (longitudinal analysis)
A

| Comedication is associated with impaired control by comparison to monotherapy
In several papers, the same results were observed: comedication is associated with worse control by comparison to monotherapy with INCS or Aze-Flu. 40,58,62,68 Days with the best control were those with no medication. The same results were observed during and outside the pollen season. In all four studies, the trends between medications were similar from the first day of reporting to long-term reporting.
However, the levels of VAS global allergy symptoms decreased largely with time in treated and untreated days ( Figure 12).

Limitations of the study:
Overall limitations.

| AIT is effective using direct patient data
Evidence regarding AIT efficacy on AR has been provided mostly by RCTs. A pilot study showed that AIT was able to improve symptoms and work productivity ( Table 6). This study suggested an additive effect of AIT over medications. 71 In a second study (submitted), it was found that AIT was more effective on days with OAH than on those with INCS (monotherapy or comedication). AIT had little effect on Aze-FLU.

Limitations of the studies:
There was no differentiation between SCIT and SLIT, and between different vaccines. This was not possible due to the number of patients and the lack of information on treatments.

| SLIT is more effective than SCIT
The reported control of AR symptoms (VAS global allergy symptoms), work (VAS work) and CSMS was studied in users receiving sublingual AIT (SLIT) or subcutaneous AIT (SCIT), and in those with no AIT. The MASK-air ® data of European users with self-reported AR and grass pollen allergy were studied. Bayesian mixed-effects models-with clustering by patient, country and pollen season-were analysed ( Figure 13). 94 Limitations of the studies: There was no differentiation between different SLIT or SCIT vaccines. This was not possible due to the number of patients.

| AIT impact on educational activities in young people differs from pharmacotherapy
Several studies have suggested an impact of AR on academic productivity. However, large studies with direct patient data are not available. We assessed variables measuring the impact of allergies on academic performance (VAS school, WPAI + CIQ:AS impact of allergy symptoms on academic performance and percentage of hours of school lost due to allergies). Additionally, factors associated with the impact of allergic symptoms on academic productivity were assessed using multivariable mixed models.
AIT showed a strong negative association with VAS school (Table 7). On the other hand, a worse rhinitis control (CSMS) was associated with worse VAS school, higher impact on academic productivity and the percentage of hours of school missed due to allergy. 69 Limitations of the studies: There was no differentiation between SCIT and SLIT and between different vaccines. This was due to the number of patients and the lack of information on treatments up until 2021.

| Adherence to SLIT appears to be better than adherence to pharmacotherapy
In a small sample (170 users), over 50% of users were fully adherent to SLIT during the pollen season.  Abbreviations: CI, confidence interval; IQR, interquartile range; Symptoms VAS, MASK-air ® visual analogue scale assessing the severity of overall allergic symptoms on that day; Work VAS, MASK-air ® visual analogue scale assessing the impact of allergic symptoms on work on that day.

| Rapid relief of symptoms by SLIT
AIT was suggested to be rapidly effective in AR. 95 In a European cross-sectional study, MASK-air ® data were assessed in patients reporting grass pollen AIT, comparing days with AIT versus days without AIT. 2296 days from 80 patients using SCIT and 3098 days from 113 patients using SLIT were analysed. In users under SLIT, days with AIT were associated with better AR control than days without AIT, with lower CSMS and VAS global ( Figure 14). Similar results were observed in sensitivity analyses.
Use of AIT could not be associated with improved AR control in patients under SCIT.
AIT is proposed to be an effective treatment for AR only after weeks or months. However, the current data indicate that it is rapidly effective. 95 As an example, rush SCIT to pollen and mites reduces skin test reactivity to allergens within days in a dose-dependent and time-   Every day, in the app, the prediction of pollens (pollution available 01-2023) is indicated for the current and for the next day ( Figure 15).

| Treatment of rhinitis alone versus rhinitis and asthma
Rhinitis alone and rhinitis and asthma represent two different diseases with differences in genetic background, 90,101 allergen sensitisation, 84,88,102 inflammation (blood eosinophils), 84 age of onset, 84,102 prevalence of conjunctivitis, 84,85 severity of rhinitis 85 and response to treatment. It is important for guidelines to reflect these findings.
However, available RCTs will not find differences without reanalysing the data on file. Moreover, since most patients in RCTs have severe symptoms, differentiating between the two phenotypes may not be easy.

| Value-Added Medicines: PRN rather than long-term (not for CRS)
Drug repurposing is one of the major fields of Value-Added Medicines. 103 These trials have shown the benefits of substituting short-acting βagonists with budesonide-formoterol as a rescue medication in mild asthma patients.

| The step-up-step-down strategy needs to be reconsidered in some patients using mHealth tools
Guidelines for rhinitis or asthma propose a step-up and step-down strategy. However, MASK-air ® studies show that, in most cases, when patients are uncontrolled, they use any medication and not the appropriate one. This suggests that a very simple approach needs to be considered for mild symptoms and for when they are getting worse.
Moreover, in AR, around 10% of patients are adherent and an alternative approach is needed for these cases with a defined stepup-step-down strategy. 107 Overall, there is an urgent need to develop an electronic clinical decision support system for patients who are not controlled with first-line treatments and who need better assessment. 30

| mHealth biomarkers in rhinitis for patient stratification and follow-up
Biomarkers that reflect biological processes are essential for moni- The new ARIA-EAACI CSMS is a validated, real-life, digitallyenabled, patient-centred biomarker for any treatment, particularly AIT. It was found to be applicable to different languages and cultures (Table 9).

By analogy with diabetes, 110 two types of mHealth biomarkers
can be defined in rhinitis ( Figure 16): � Daily monitoring of the control (analogous to glycemia measurement): ARIA-EAACI CSMS � Longer-term monitoring using control scores (analogous to Hb1AC measurement): CARAT. 32,43,111 For this approach to extend to asthma, a CSMS assessing short-term asthma control needs to be developed.
In AIT, the allergy-CSMS can be used to (i) stratify patients (uncontrolled days during the allergen exposure, e.g., pollen season, despite guideline-based treatment in patients adherent to treatment), (ii) propose an early stopping rule, (iii) follow the patient during the treatment and (iv) follow the patient during the after-cessation follow-up ( Figure 16). However, a dual approach can be proposed combining the daily allergy-CSMS with a control test for allergic diseases assessing at least 1 month of survey.

| Optimisation of shared decision making
In shared decision making (SDM), both the patient and the physician contribute to the medical decision-making process, placing the patient at the centre of the decision paradigm. 112,113 An innovation in SDM is the use of mHealth evidence-based tools that can inform patient decisions based on a guided self-management plan proposed by their healthcare professional. 114 In MASK-air ® , an e-CDSS has been devised. 30 However, it has not yet been implemented because it needed an MDR Class IIa accreditation (January 2022) after ethical approval. mHealth biomarkers for daily and long-term control will help SDM.
In daily practice, MASK-air ® can be used for the optimisation of SDM since the physician can obtain the daily information of medication and control when the patient is consulting. 82

| School, work and economic impacts
In MASK-air ® , several outcomes have an economic impact: EQ-5D VAS, Work VAS and WPAI-AS. 48,53,59 Combining these data, a plan is being devised to ascribe an economic impact to CSMS.  guidelines in rhinitis and asthma using real-world evidence. 115 However, these recommendations were based on a consensus.

|
The NextGen ARIA guidelines 2023 will be developed with real patient data, analysis of new data and new methods facilitating the process of prioritising questions and health outcomes in guideline development. This will support the creation of trustworthy guidelines following a structured plan (in collaboration with HJ Schünemann and J Brozek): [116][117][118][119][120] � Question prioritisation including, if possible, (i) differentiation between rhinitis and asthma + rhinitis, (ii) comedication and (iii) AIT.
� Evidence-based analysis including meta-analyses.
� Integration of direct patient data including MASK-air ® .
� GRADE Evidence to Decision (EtD) frameworks. 121 It is expected that the NextGen ARIA guidelines 2023 will be developed in collaboration with OECD, Fraunhofer and several scientific and patient organisations. 11.9 | Change management and political agenda for digitally-enabled, patient-centred care pathways ARIA has evolved from a guideline using the best approach 124 to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. 125 The proposed next phase of ARIA is change management. 126 The aim of this phase is to provide an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle, irrespective of their sex or socioeconomic status. The aim is to reduce health and social inequities incurred by the disease. ARIA will follow the 8-step model of Kotter (i) to assess and implement the effect of rhinitis on asthma multimorbidity and (ii) to propose NextGen guidelines. These guidelines will need to be presented to regulators and payers and this may be possible through the OECD.